title: A recurrent deletion of DPY19L2 causes infertility in man by blocking sperm head elongation and acrosome formation.
abstract: An increasing number of couples require medical assistance to achieve a pregnancy, and more than 2% of the births in Western countries now result from assisted reproductive technologies. To identify genetic variants responsible for male infertility, we performed a whole-genome SNP scan on patients presenting with total globozoospermia, a primary infertility phenotype characterized by the presence of 100% round acrosomeless spermatozoa in the ejaculate. This strategy allowed us to identify in most patients (15/20) a 200 kb homozygous deletion encompassing only DPY19L2, which is highly expressed in the testis. Although there was no known function for DPY19L2 in humans, previous work indicated that its ortholog in C. elegans is involved in cell polarity. In man, the DPY19L2 region has been described as a copy-number variant (CNV) found to be duplicated and heterozygously deleted in healthy individuals. We show here that the breakpoints of the deletions are located on a highly homologous 28 kb low copy repeat (LCR) sequence present on each side of DPY19L2, indicating that the identified deletions were probably produced by nonallelic homologous recombination (NAHR) between these two regions. We demonstrate that patients with globozoospermia have a homozygous deletion of DPY19L2, thus indicating that DPY19L2 is necessary in men for sperm head elongation and acrosome formation. A molecular diagnosis can now be proposed to affected men; the presence of the deletion confirms the diagnosis of globozoospermia and assigns a poor prognosis for the success of in vitro fertilization.
authors.affiliation: Faculté de Médecine-Pharmacie de Grenoble, Université Joseph Fourier, Domaine de la Merci, Grenoble, France.
authors.forename: Radu
authors.initials: R
authors.lastname: Harbuz
authors.forename: Raoudha
authors.initials: R
authors.lastname: Zouari
authors.forename: Virginie
authors.initials: V
authors.lastname: Pierre
authors.forename: Mariem
authors.initials: M
authors.lastname: Ben Khelifa
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Kharouf
authors.forename: Charles
authors.initials: C
authors.lastname: Coutton
authors.forename: Ghaya
authors.initials: G
authors.lastname: Merdassi
authors.forename: Farid
authors.initials: F
authors.lastname: Abada
authors.forename: Jessica
authors.initials: J
authors.lastname: Escoffier
authors.forename: Yorgos
authors.initials: Y
authors.lastname: Nikas
authors.forename: François
authors.initials: F
authors.lastname: Vialard
authors.forename: Isabelle
authors.initials: I
authors.lastname: Koscinski
authors.forename: Chema
authors.initials: C
authors.lastname: Triki
authors.forename: Nathalie
authors.initials: N
authors.lastname: Sermondade
authors.forename: Thérèse
authors.initials: T
authors.lastname: Schweitzer
authors.forename: Amel
authors.initials: A
authors.lastname: Zhioua
authors.forename: Fethi
authors.initials: F
authors.lastname: Zhioua
authors.forename: Habib
authors.initials: H
authors.lastname: Latrous
authors.forename: Lazhar
authors.initials: L
authors.lastname: Halouani
authors.forename: Marrakchi
authors.initials: M
authors.lastname: Ouafi
authors.forename: Mounir
authors.initials: M
authors.lastname: Makni
authors.forename: Pierre-Simon
authors.initials: PS
authors.lastname: Jouk
authors.forename: Bernard
authors.initials: B
authors.lastname: Sèle
authors.forename: Sylviane
authors.initials: S
authors.lastname: Hennebicq
authors.forename: Véronique
authors.initials: V
authors.lastname: Satre
authors.forename: Stéphane
authors.initials: S
authors.lastname: Viville
authors.forename: Christophe
authors.initials: C
authors.lastname: Arnoult
authors.forename: Joël
authors.initials: J
authors.lastname: Lunardi
authors.forename: Pierre F
authors.initials: PF
authors.lastname: Ray
mesh_terms: D000177:Acrosome / Q000378:metabolism / Q000473:pathology*; D056915:DNA Copy Number Variations / Q000235:genetics; D005190:Family; D005260:Female; D017353:Gene Deletion; D008040:Genetic Linkage; D056426:Genetic Loci / Q000235:genetics; D006720:Homozygote; D006801:Humans; D007248:Infertility, Male / Q000235:genetics*; D007597:Jordan; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D010375:Pedigree; D013077:Sperm Head / Q000378:metabolism / Q000473:pathology*
chemical_list: C511317:DPY19L2 protein, human; D008565:Membrane Proteins